Chimpanzees were immunized with a formalin inactivated or an acellular extract vaccine by the intraperitoneal-priming, intratracheal-booster immunization schedule shown previously to protect hamsters on challenge (Barile et al., 1988b). Although immunization with either vaccine induced some seroconversion, there was only a slight increase in the serum specific IgM values, and no increase in IgG values. Following immunization, there was little or no increase in the specific IgA or IgG values in lung lavage fluids. Thus, these two vaccines did not induce a meaningful immunological response. Two weeks after immunization, animals were challenge with 1 x 107 CCU of virulent strain PI-1428. Mean antibody titers for the acellular vaccine-immunized animals peaked within four weeks at 1:256, and then declined, whereas the formalin-inactivated vaccine animals' titers peaked at 1:85 within six weeks and persisted throughout the 10 week study period. The oropharygeal, tracheal and lung tissues of immunized and non-immunized animals became colonized, and peak titers ranged from 106 to 108 CCU/ ml. The animals immunized with either vaccine developed less colonization of the oropharynx and a lesser amount of overt disease than the non-immunized controls. The formalin inactivated vaccine that was used in a field trial study protected 67% of the vaccinees (Wenzel et al., 1977), and provided partial protection to these chimpanzees on challenge. Prior to challenge, the serum antibody titers of two chimpanzees experimentally infected six months earlier with M. pneumoniae were both 1:64. Following challenge, the mean antibody titer peaked at 144 within two weeks, and then declined. The oropharygeal, tracheal and lung tissues of one chimpanzee did not become colonized and the other animal had only one positive culture, a lung specimen with a titer of only 102 CCU/ml. These findings indicate that a prior mycoplasmal infection protects the animal host against subsequent challenge or exposure.